Doctors currently struggle to determine whether a breast
tumor is likely to shift into an aggressive, life-threatening mode—an issue
with profound implications for treatment. Now a group from The Scripps Research
Institute (TSRI) has identified a mechanism through which mitochondria, the
powerhouses of a cell, control tumor aggressiveness. Based on their findings,
the team developed a simple treatment that inhibits cancer progression and
prolongs life when tested in mice.

The research team, which describes its results February 15,
2013, in an article published online ahead of print by TheJournal of
Clinical Investigation, hopes to proceed quickly to human clinical trials
to test this new approach using drugs already in use for other conditions.

Looking at Clues

The TSRI laboratory of Associate Professor Brunhilde H.
Felding studies cancer, especially the mechanisms that control metastasis, the
spread of cancer from its primary site to distant organs in the body.

Past research suggested that mutations affecting
mitochondria, which are key to energy production in cells, strongly influence
whether a tumor becomes aggressive. But the mechanism was not clear.

“We decided to investigate a specific protein complex,
called mitochondrial complex I, that critically determines the energy output of
cellular respiration,” said the study’s first author, Antonio F. Santidrian, a research
associate in Felding’s laboratory.

To do this, the group teamed up with Akemi and Takao Yagi at
TSRI, who are leading experts in complex I research. Using unique reagents from
the Yagi group, the Felding team discovered that the balance of key metabolic
cofactors processed by complex I—specifically, nicotinamide adenine
dinucleotide (NAD+) and NADH, the form it takes after accepting a
key electron in the energy production cycle—was disturbed in aggressive breast
cancer cells.

Exciting Results

To find out if the balance of NAD+ and NADH was
critical for tumor cell behavior, the team proceeded to insert a yeast gene
into cancer cells that caused a shift toward more NAD+. To the
scientists’ amazement, this shift caused the tumor cells to become less
aggressive.

“It was a really happy moment for me,” said Santidrian. But
the more exciting moments, he said, were yet to come.

To confirm and extend the initial findings, the team altered
genes tied to NAD+ production. The resulting shift again showed that
higher NADH levels meant more aggressive tumors, while increased NAD+
had the opposite effect.

The next logical step was to find a simple way to enhance
the critical NAD+ level therapeutically. So the team explored what
would happen if mice with breast cancer were fed water spiked with
nicotinamide, a precursor for NAD+ production. The scientists found cancer
development was dramatically slowed down, and the mice lived longer

“In animal models at various stages, we see that we can
actually prevent progression of the disease,” said Felding.

Next Steps

Now the group is working toward human trials to learn
whether nicotinamide or other NAD+ precursors will have similarly
impressive results in humans. Since NAD+ precursors are already used
for other purposes, such as controlling cholesterol levels, achieving approval
for human clinical trials should be simpler than is normally the case.

“It is not a totally new treatment that would need to be
tested for toxicity and side effects like a new drug,” said Felding. “And we
already know the precursors can be easily ingested.”

If manipulating the NAD+/NADH ratio in humans has
the same effect as in mice, the results could be profound. Such treatment could
benefit people at risk of developing aggressive breast cancer, offer
complimentary treatment to chemo and radiation therapy to avoid disease
recurrence, and maybe even provide a preventive treatment for women with a
family history of breast cancer.

This research was funded by grants from the National
Institutes of Health (R01CA112287, R01CA170737, R01CA170140, UL1RR025774 and
R01DK053244), the US Department of Defense (W81XWH-08-0468), the California
Breast Cancer Research Program (17NB-0058, 16IB-0052, 12NB-0176 and 13NB-0180),
and the Susan G. Komen Foundation, as well as a donation from Las Patronas.

In addition to Santidrian and Felding, authors of the paper,
titled, “Mitochondrial Complex I activity and NAD+/NADH balance
regulate breast cancer progression,” were Akemi Matsuno-Yagi, Melissa Ritland,
Byoung B. Seo, Sarah E. LeBoeuf, Laurie Gay, and Takao Yagi, all from TSRI. For
further information on the paper, see http://www.jci.org/articles/view/64264.

Send comments to: press[at]scripps.edu

Associate Professor Brunhilde H. Felding, Research Associate
Antonio F. Santidrian and colleagues have developed a
simple treatment that inhibits cancer progression and prolongs life when tested
in mice. (Photo by Cindy Brauer.)